Novel antioxidants’ synthesis and their anti-oxidative activity through activating Nrf2 signaling pathway

• Published in: Bioorganic & medicinal chemistry letters 2017-04, Vol.27 (7), p.1616-1619
• Main Authors: Wu, Jianzhang, Ren, Jiye, Yao, Song, Wang, Jiabing, Huang, Lili, Zhou, Peng, Yun, Di, Xu, Qing, Wu, Shoubiao, Wang, Zhankun, Qiu, Peihong
• Format: Article
• Language: English
• Subjects: Animals; Antioxidant; Antioxidants - chemical synthesis; Antioxidants - pharmacology; Antipyrine - analogs & derivatives; Antipyrine - pharmacology; Apoptosis - drug effects; Buthionine Sulfoximine - pharmacology; GCLC; Glutamate-Cysteine Ligase - antagonists & inhibitors; Glutamate-Cysteine Ligase - genetics; Glutamate-Cysteine Ligase - metabolism; Hydrogen Peroxide - pharmacology; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative Stress - drug effects; PC12; PC12 Cells; Protective Agents - chemical synthesis; Protective Agents - pharmacology; Protein Transport; Rats; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; Signal Transduction; Up-Regulation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.02.006

[Display omitted] Novel structure compounds (WS) containing 3,4,5-trimethoxyphenyl and acyl pyrazole were designed and synthesized based combination principles. Among them, WS13 was screened out to possess desirable anti-oxidative activity in vitro. Cell survival assay and apoptosis experiment in H2O2 induced PC12 cells injury model all showed that its cytoprotection exhibited a concentration-effect manner. WS13 at 10μM could remove ROS with equal effiency to edaravone. Further, it clearly activated Nrf2 nuclear translocation and upregulated GCLC mRNA transcription and protein expression in dose-dependent manner, and its cytoprotection was reversed by GCLC protein inhibitor. In total, WS13 with further promotion can serve as Nrf2-GCLC activator in anti-oxidative therapy.